The present invention is directed to novel 2phenyl-5thiophenyl-2,4-dihydro-[1,2,4]-triazol-3-one derivatives which are smooth muscle relaxants and therefore are useful in treating disorders responsive to relaxation of smooth muscle such as asthma, irritable bowel syndrome, male erectile dysfunction and particularly urinary incontinence. The present invention is also directed to a method of treatment with the novel compounds and to pharmaceutical compositions containing them.
Urinary incontinence is a common condition that is the frequent cause of confinement to nursing homes among the elderly. It afflicts significant numbers among both men and women and all ages. In addition studies show some degree of daily incontinence reported among as many as 17% of young apparently healthy women. Safe and reliable methods for treating incontinence are clearly needed. Urinary incontinence is a manifestation of the failure to control the muscles of the bladder or urinary sphincter. Incontinence results when the pressure within the bladder is too great as a result of excessive force exerted by the bladder muscles, or when the sphincter muscles are too weak. Urinary incontinence can be a manifestation of other diseases such as Parkinsonism, multiple sclerosis, lesions of the central nervous system, or bladder infections. Interstitial cysts can result in instability of the bladder detusor muscles and a particularly unpleasant form of urge incontinence. Urinary incontinence is believed to currently affect over 12 million people in the United States alone, and to occur in between 15 and 30% of the population over 60. The current standard of care is quite unsatisfactory. All of the current drugs now utilized to treat urinary incontinence suffer from polypharmacology and unwanted side effects.
Relaxation of the smooth muscle tissue of the bladder results in a decrease in the pressure within the bladder. Relaxation of the smooth muscle tissue of the bladder would therefore be desirable to treat urinary incontinence which results when the pressure within the bladder is too great as a result of excessive force exerted by the bladder muscles. Relaxation of other smooth muscle tissues may also result in alleviation of diseases or disorders in which excessive smooth muscle contraction has been implicated such as asthma, irritable bowel syndrome, male erectile dysfunction.
The present invention provides novel 2phenyl-5thiophenyl-2,4-dihydro-[1,2,4]-triazol-3-one derivatives which have been found to be smooth muscle relaxants. The present invention also provides compositions containing the novel 2phenyl-5thiophenyl-2,4-dihydro-[1,2,4]-triazol-3-one derivatives and a method of treating diseases or disorders responsive to the relaxation of smooth muscle tissue such as asthma, irritable bowel syndrome, male erectile dysfunction and particularly urinary incontinence.
U.S. Pat. No. 5,869,509, issued Feb. 9, 1999, provides novel diphenyl heterocyclic derivatives having the general formula 
wherein xe2x80x9cHetxe2x80x9d is a moiety selected from the group consisting of (A) through (H): 
wherein Z is independently for each occurrence selected from O or S; Ra, Rb and Rc each are independently selected from hydrogen, halogen, OH, CF3, NO2, or 
provided Rc is not hydrogen; and when Ra and Rb are hydrogen, Rc may be a heterocyclic moiety selected from the group consisting of imidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl, and pyridin-2-yl; Rd and Re each are independently selected from hydrogen, halogen, CF3, NO2 or imidazol-1-yl; m, n and p each are independently selected from 0 or 1; and Rf and Rg each are independently hydrogen; C1-4 alkyl; or Rf and Rg, taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety selected from the group consisting of N-methylpiperazine, morpholine, thiomorpholine, N-benzylpiperazine and imidazolinone.
A method for preparing [1,2,4]-2,4-dihydrotriazolones was disclosed in J. Org. Chem. 1976, 41, 3233-3237, including a single thiophen-2-yl derivative, 2phenyl-5thiophen-2-yl-2,4-dihydro-[1,2,4]triazol-3-one, shown below. Nippon Kagaku Zasshi 1968, 89, 69-74 also discloses 2phenyl-5thiophen-2-yl-2,4-dihydro-[1,2,4]triazol-3-one, prepared by the ring closure reaction of the corresponding 1-aryl-4-acyl semicarbazide. 
A method to oxidize oxadiazoles to provide [1,2,4]-2,4-dihydrotriazolones was reported in J. Heterocyclic Chem. 1985, 22, 1383-1388. The four 5-(5-nitrothiophen-2-yl)-2,4-diphenyl-2,4-dihydro-[1,2,4]triazol-3-one derivatives shown below were disclosed in this publication. 
International Application WO9954315, published Oct. 28,1999, discloses triazolones of the general formula shown below, which act as neuroprotectants. In the general structure 
R2 may be a carbon linked 5 or 6-membered saturated or unsaturated heterocycle, such that 1, 2, 3, or 4 atoms can be chosen from oxygen, nitrogen or sulfur and the substituents can be C1-6alkyl or benzyl. R1 may be phenyl or substituted phenyl.
Novel compounds of formula I are useful to treat disorders responsive to relaxation of smooth muscle: 
wherein:
Q is 
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl and C2-6alkenyl;
R3 is halogen or trifluoromethyl; and
R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen and C1-6alkyl;
or a nontoxic pharmaceutically acceptable salt or solvate thereof. The present invention also provides pharmaceutical compositions thereof and methods which employ them.
The term xe2x80x9cC1-6 alkylxe2x80x9d as used herein and in the claims (unless the context indicates otherwise) means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, 3-methylbutyl, hexyl and the like. The term xe2x80x9cC2-6 alkenylxe2x80x9d as used herein and in the claims (unless the context indicates otherwise) means straight or branched chain alkenyl groups such as ethenyl (i.e. vinyl), propenyl, allyl, butenyl, 3-methylbutenyl, pentenyl, hexenyl and the like. Unless otherwise specified, the term xe2x80x9chalogenxe2x80x9d as used herein and in the claims is intended to include bromine, chlorine, iodine and fluorine while the term xe2x80x9chalidexe2x80x9d is intended to include bromide, chloride and iodide anion.
The term xe2x80x9cnontoxic pharmaceutically acceptable saltxe2x80x9d as used herein and in the claims is intended to include nontoxic acid and base addition salts. Suitable acids include sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, cinnamic, fumaric, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, heptanoic, and the like. Suitable inorganic bases, such as alkali and alkaline earth metal bases, include metallic cations such as sodium, potassium, magnesium, calcium and the like.
Generally, pharmaceutically acceptable salts of the invention are those in which the counter-ion does not contribute significantly to the toxicity or pharmacological activity of the salt. In some instances, they have physical properties which make them more desirable for pharmaceutical formulations, such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The salts are routinely made by admixture of a Formula I compound with the selected acid or base, preferably by contact in solution employing an excess of commonly used inert solvents such as water, ether, benzene, methanol, ethanol, ethyl acetate and acetonitrile. They may also be made by metathesis or treatment with an ion exchange resin under conditions in which the appropriate ion of a salt of the substance of the Formula I is replaced by another ion under conditions which allow for separation of the desired species such as by precipitation from solution or extraction into a solvent, or elution from or retention on an ion exchange resin.
Certain compounds of the present invention can exist as solvated forms including hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. The products may be true solvates, while in other cases, the products may merely retain adventitious solvent or be a mixture of solvate plus some adventitious solvent. It should be appreciated by those skilled in the art that solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
In the method of the present invention, the term xe2x80x9ctherapeutically effective amountxe2x80x9d means the total amount of each active component of the composition that is sufficient to show a meaningful patient benefit, i.e., healing of acute conditions characterized by relaxation of smooth muscle or increase in the rate of healing of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. The terms xe2x80x9ctreat, treating, treatmentxe2x80x9d as used herein and in the claims means preventing or ameliorating diseases, tissue damage and/or symptoms associated with constriction of smooth muscle tissue by administration of a compound of Formula I.
The compounds of Formula I and intermediates useful for their synthesis may be prepared by various procedures such as those illustrated herein in the examples, in the Reaction Schemes, and by variations thereof which would be evident to those skilled in the art.
Intermediates useful for the preparation of compounds of Formula I may be prepared by the procedures outlined in Reaction Schemes I-V. 
Reaction Scheme I depicts the preparation of a (2-methoxyphenyl)hydrazine derivative III from the corresponding 2-methoxyaniline derivative V. The (2-methoxyphenyl)hydrazine derivative III may be prepared by treatment of a solution of the corresponding 2-methoxyaniline derivative V (1.0 equivalent) in concentrated hydrochloric acid (concentration approximately 0.27 M) with aqueous sodium nitrite (1.3 equivalents, concentration approximately 3.5 M) at approximately xe2x88x9210xc2x0 C. The resulting mixture is stirred at 0xc2x0 C. for approximately one hour then cooled to xe2x88x9235xc2x0 C. and treated with a solution of Tin(II) chloride dihydrate in concentrated hydrochloric acid (2.6 equivalents, concentration 4.0 M). The reaction mixture is stirred at 0xc2x0 C. for one hour then the resulting solid is collected by filtration and washed with concentrated hydrochloric acid and water. The resulting solid is then stirred in a mixture of an appropriate solvent such as ethyl acetate or dichloromethane and aqueous sodium hydroxide (typically 2M or 3 M). The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo to provide the (2-methoxyphenyl)hydrazine derivative III. 
Reaction Scheme II depicts the preparation of a (2-methoxyphenyl)hydrazine derivative III from the corresponding (2-methoxyphenyl)diazo salt derivative VI (X represents a halide such as chloride). A solution of the (2-methoxyphenyl)diazo salt derivative VI in concentrated hydrochloric acid is treated with a solution of Tin(II) chloride dihydrate in concentrated hydrochloric acid as described previously for Reaction Scheme I. After workup, as described for Reaction Scheme I, the (2-methoxyphenyl)hydrazine derivative III may be obtained. 
Reaction Scheme III shows the preparation of thiophenyl oxo-acetic acid derivatives IV, IVa and IVb from the corresponding appropriate thiophene derivatives VIII, VIIIa and VIIIb (equations 1-3, respectively). A mixture of an appropriate thiophene derivative such as VIII, VIIIa or VIIIb (1.0 equivalent) and ethyl oxalyl chloride (1.5 equivalents) may be treated with a solution of aluminum trichloride in nitromethane (1.5 equivalents, concentration approximately 3.6 M) at a temperature of approximately 0-10xc2x0 C. The reaction mixture is stirred at approximately 0xc2x0 C. for one hour, room temperature for three hours and then poured into ice water. The resulting mixture is then extracted with an appropriate solvent such as diethyl ether. The organic layer is washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is typically purified by either distillation or flash chromatography on silica gel to provide the thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb, respectively.
The thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb may be subjected to hydrolysis to provide the corresponding thiophenyl oxo-acetic acid IV, IVa or IVb. The hydrolysis may be carried out under either acidic or basic conditions. Basic hydrolysis can typically be carried out by treating a solution of a thiophenyl oxo-acetic acid ethyl ester such as VII, VIIa or VIIb (1.0 equivalent) in an aqueous mixture of an appropriate solvent such as methanol, tetrahydrofuran or 1,4-dioxane with a suitable base such as aqueous sodium hydroxide or potassium hydroxide (typically 1.5 equivalents) for a period of four to twenty hours at a temperature range of 0xc2x0 C. to room temperature. The reaction mixture can be worked up by acidification with an appropriate acid such as hydrochloric acid or acetic acid followed by extraction with an appropriate solvent such as ethyl acetate or dichloromethane. The resulting organic layer may then be concentrated in vacuo to provide the thiophenyl oxo-acetic acid IV, IVa or IVb, respectively. If desired, the thiophenyl oxo-acetic acid IV, IVa or IVb could then be further purified by recrystallization or preparative HPLC. Alternatively, the hydrolysis of the thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb to the corresponding thiophenyl oxo-acetic acid IV, IVa or IVb may be carried out under acidic conditions. The acidic hydrolysis is typically carried out by refluxing a thiophenyl oxo-acetic acid ethyl ester such as VII, VIIa or VIIb in a mixture of acetone and water in the presence of hydrochloric acid for one to four hours. The reaction mixture is then extracted with an appropriate solvent such as dichloromethane and the organic layer concentrated in vacuo to provide the thiophenyl oxo-acetic acid IV, IVa and IVb, respectively. 
Reaction Scheme IV depicts an alternative route to the preparation of thiophenyl oxo-acetic acid derivatives IV, IVa and IVb (equations 1-3, respectively). One equivalent of an appropriate acetyl thiophene derivative such as IX, IXa or IXb can be treated with selenium dioxide (1.5 equivalents) in pyridine at approximately 70xc2x0 C. for three hours. The reaction mixture is allowed to cool to room temperature and then poured into 1N HCl. The resulting mixture is extracted with an appropriate solvent such as diethyl ether. The organic layer can then be dried over anhydrous sodium sulfate and concentrated in vacuo to provide the thiophenyl oxo-acetic acid derivatives IV, IVa and IVb, respectively. The products thus obtained can be further purified by standard techniques such as recrystallization or preparative HPLC. 
The 2-(2-methoxyphenyl)-5thiophenyl-2,4-dihydro-[1,2,4]-triazol-3-one derivatives of Formulae II, IIa and IIb can be prepared as depicted in Reaction Scheme V (equations 1-3, respectively). An appropriate thiophenyl-oxo-acetic acid such as IV, IVa or IVb (1.0 equivalent) and a (2-methoxyphenyl)hydrazine derivative III (1.0 equivalent) is refluxed in acetonitrile (15-25 mL/mmol starting material) for 30-60 min. The reaction is cooled to room temperature then triethylamine (1.1 equivalent) and diphenylphosphorylazide (1.1 equivalent) is added, and the reaction heated at reflux for a period of approximately 3 to 18 hours. After cooling to room temperature, solids are collected by filtration and washed with acetonitrile and diethyl ether to provide the corresponding 2-(2-methoxyphenyl)-5thiophenyl-2,4-dihydro-[1,2,4]-triazol-3-one II, IIa or IIb. If necessary, the product is further purified by standard techniques such as flash chromatography on silica gel 60 typically eluted with hexane/ethyl acetate.
The compounds of Formula I were prepared according to the methods depicted below in Schemes VI. 
Reaction Scheme VI depicts the preparation of compounds of Formulae I, Ia and Ib from the corresponding intermediates of formulae II, IIa and IIb, respectively. The triazolone methyl ether of formulae II, IIa or IIb (1.0 equivalent) is suspended in anhydrous dichloromethane (20-25 ml/mmol of formulae II, IIa or IIb) under argon and cooled to xe2x88x9278xc2x0 C. A 1M solution of boron tribromide (BBr3, 2-3 equivalents) in anhydrous dichloromethane is added via a dropping funnel over a 45 minute period. After the addition is complete, the reaction is warmed to room temperature and stirred for approximately 5 hours. The reaction may be quenched by the addition of water (typically 5-10 ml). Volatile solvent is removed under vacuum and the crude product filtered and washed with water, then heated in a mixture of acetone and ethanol for approximately 15 minutes. After cooling to room temperature, the purified product is filtered and washed with acetone and ethanol. The solid is dried under high vacuum to provide the corresponding products of formulae I, Ia or Ib, respectively. If necessary, the product can be further purified by recrystallization from an appropriate solvent such as tetrahydrofuran.
Compounds of Formula I, Ia or Ib may contain an allyl group (CH2CHxe2x95x90CH2) at the positions designated R1 or R2. The allyl group at the R1 or R2 position of a compound of Formula I, Ia or Ib may be isomerized by treatment with rhodium trichloride dihydrate in refluxing ethanol to provide the corresponding prop-1-en-1-yl (CHxe2x95x90CHCH3) derivative. The allyl group at the R1 or R2 position of a compound of Formula I, Ia or Ib may also be reduced by hydrogenation using 10%Pt(S)/C catalyst in ethanol at 50 psi for 3 hours.
In a preferred embodiment of the invention are compounds of Formula Ic 
wherein R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen and C1-6alkyl; or a nontoxic pharmaceutically acceptable salt or solvate thereof.
In another preferred embodiment of the invention are compounds of Formula Id 
wherein R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen and C1-6alkyl; or a nontoxic pharmaceutically acceptable salt or solvate thereof. A more preferred embodiment is a compound of Formula Id wherein R4 and R6 are halogen and R5 is hydrogen.
In yet another preferred embodiment of the present invention are compounds of Formula Ie 
wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl and C2-6alkenyl; R3 is halogen or trifluoromethyl; or a nontoxic pharmaceutically acceptable salt or solvate thereof.
In still yet another preferred embodiment of the present invention are compounds of Formula If 
wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl and C2-6alkenyl; R3 is halogen or trifluoromethyl; or a nontoxic pharmaceutically acceptable salt or solvate thereof.
In another aspect, this invention provides a method for the treatment of disorders responsive to relaxation of smooth muscle in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, or a nontoxic pharmaceutically acceptable salt thereof. Preferably, the compounds of Formula I are useful in the treatment of urinary incontinence, asthma, irritable bowel syndrome or male erectile dysfunction and more preferably in the treatment of urinary incontinence.
In still another aspect, this invention provides pharmaceutical compositions comprising at least one compound of Formula I in combination with a pharmaceutically acceptable adjuvant, carrier or diluent.
Smooth muscle tissue is present in mammals in the lung, bowel, male genitalia and bladder. Abnormal smooth muscle contractions in these tissues can therefore cause certain types of asthma, irritable bowel syndrome, male sexual dysfunction and urinary incontinence. For example, urge urinary incontinence (UUI) is the most prevalent type of urinary incontinence and is characterized by abnormal spontaneous bladder smooth muscle contractions, which arise during bladder filling. Urge urinary incontinence (UUI) may therefore be treated with compounds which partially inhibit contractions of the bladder smooth (detrusor) muscle. Likewise, partial inhibition of contractions in smooth muscle tissue present in the mammalian lung, bowel and male genitalia may provide effective treatment for disorders such as asthma, irritable bowel syndrome and male erectile dysfunction, respectively.
The ability of the compounds of the present invention to relax smooth muscle tissue was assessed by their ability to inhibit carbachol induced contractions in mammalian smooth muscle tissue. More specifically, the compounds of the present invention were screened in an in vitro rat bladder strip model to estimate their inhibitory effects on 10 xcexcM carbachol induced contraction of the rat bladder strip according to the following experimental protocol.
Experimental Protocol
1. Bladder Strip Tissue Preparation
Male rats were sacrificed by decapitation, the bladder removed and cleaned of connective tissue. Strips of bladder were then cut from the bladder body and placed in organ baths, suspended between a fixed hook and a force transducer, containing oxygenated physiological buffer maintained at 37xc2x0 C.
2. Experimental Design
The bladder strips were primed by stimulating them with 10 xcexcM carbachol to evoke a contraction. The strips were then washed multiple times with fresh physiological buffer and allowed to fully relax. Following a period of recovery, the strips were again challenged with 10 xcexcM carbachol to produce a contraction; this contractile response served as control response. The strips were again washed multiple times and allowed to fully relax (45 minutes). Test compound (3 xcexcM) or vehicle was then added to each organ bath. Following a one hour incubation period, the strips were again stimulated with 10 xcexcM carbachol and the contractile response measured.
3. Data Analysis
The percent inhibition of the carbachol response by the test compounds was calculated by comparing control and post-compound carbachol responses normalized for vehicle effects. The percentage inhibition for each compound at 3 xcexcM concentration is provided below in Table 1.
The results of the above biological test demonstrate that the compounds of the present invention are effective inhibitors of the 10 xcexcM carbachol induced rat bladder contractions as these contractions were inhibited within the range of 5 to 50 percent. Thus, the compounds of the present invention are useful as smooth muscle relaxants in mammals, particularly in humans, for the treatment of disorders responsive to smooth muscle relaxation such as asthma, irritable bowel syndrome, male erectile dysfunction and particularly urinary incontinence.
In yet another embodiment, this invention relates to a method for treating disorders responsive to relaxation of smooth muscle tissue in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I or a non-toxic pharmaceutically acceptable salt, solvate or hydrate thereof.
For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.
The pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formula I directly in parenteral formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example, Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.
The dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that the unit dosage form would be adjusted accordingly by one skilled in the art to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.
A suitable dose of a compound of Formula I or pharmaceutical composition thereof for a mammal, including man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0.1 xcexcg/kg to 100 mg/kg body weight. For parenteral administration, the dose may be in the range of 1 xcexcg/kg to 100 mg/kg body weight for intravenous administration. The active ingredient will preferably be administered either continuously or in equal doses from one to four times a day. However, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the choice of compound of be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient""s symptoms.